PMNs are a critical element of the innate immune system and provide a rapid first line of defense against invading pathogens. This is highlighted by the often fatal consequences of hereditary impairment of PMN function. The traditional view of PMNs as terminally differentiated, short-lived cells, without the ability to synthesize cytokines de novo has become outmoded. Furthermore, recent data provides evidence of a role for PMNs in the bridging of innate immunity with adaptive responses. We hypothesize that gender and steroid sex hormones play an important role in manipulating the innate immune system by influencing PMN functional capacities. Such alterations may have a profound impact on both host defense and responses to self. We further postulate that circulating PMNs are functionally and phenotypically different from those in tissues. This Project will address these hypotheses by investigating, using both peripheral blood PMNs and PMNs within tissues, the influence of gender and microenvironment and the extent of, and mechanisms associated with, steroid sex hormone regulation of: PMN transendothelial migration; PMN effector functions including, phagocytosis, oxidative burst metabolism, degranulation and cytokine/chemokine synthesis and release; and PMN longevity and apoptosis. The effects of transendothelial migration on PMN effector function (Specific Aim 2) and longevity (Specific Aim 3) will also be investigated in the context of gender and steroid sex hormone influences. The results of these studies may contribute important information to understanding the links between the endocrine and innate immune systems. These studies also may provide us with valuable insight into how gender and sex steroid hormones may shape innate immune responses and confer susceptibilities to infections and the development of autoimmune conditions.